Partial STAT5 signaling is sufficient for CD4⁺ T cell priming but not memory formation

Signal transducer and activator of transcription 5 (STAT5) plays an important role in regulating gene expression in response to cytokines of the common (γc) chain family. In this capacity, STAT5 promotes CD8⁺ effector and memory T cell survival and regulatory T cell development. However, its function in conventional CD4⁺ T cells is less clear. In this study, the requirement of intact STAT5 signaling for CD4⁺ effector and memory T cell generation and maintenance was investigated by using DO11.10 TCR transgenic T cells that are genetically deficient in STAT5A or B, as well as by transducing DO11 T cells with a dominant-negative STAT5 to temporally block STAT5 function. We found that the presence of STAT5A or B alone was sufficient for primary CD4⁺ effector T cell generation, but not for establishing a long-lived memory cell population. Similarly, blocking STAT5 signaling during priming did not prevent initial T cell activation, but inhibited the generation of memory cells. Surprisingly, blocking STAT5 post-priming did not impact the long-term survival of CD4⁺ memory T cells in vivo. Mechanistically, intact STAT5B, but not STAT5A, was required for IL-7Rα re-expression in activated T cells, which is an important cytokine receptor for CD4⁺ memory generation. These data show that fully functional STAT5 is essential to deliver an early, non-redundant signal for memory programming during the primary CD4⁺ T cell response, while partial STAT5 signaling is sufficient for effector differentiation. Our results have implications for the precise use of STAT5 inhibitors to timely inhibit memory T cell responses.